Tamoxifen citrate is the non-proprietary name for the compound (Z)-2-[4-(1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethylethylamine 2-hydroxy-1,2,3-propanetricarboxylic acid. The compound is used in the treatment and prevention of breast cancer, and is believed to exert its anti-tumor effect through action as an anti-estrogen at estrogen binding sites in breast tissue. The compound and its preparation are described, for example, in U.S. Pat. No. 4,536,516.
Existing commercial formulations of tamoxifen citrate, such as NOLVADEX.RTM. (produced by Zeneca Pharmaceuticals, Wilmington Del., USA) and NOLVADEX.RTM. D (produced by Zeneca Limited, Macclesfield Cheshire, United Kingdom), contain 10 mg or 20 mg of the active ingredient, tamoxifen. Based on the results of clinical studies, it is believed that the optimum dose is 20 mg per day, which may be achieved by administering 10 mg tablets twice a day or a 20 mg tablet once a day.
Tamoxifen citrate is a compound with relatively poor solubility.
Formulations of a compound with relatively poor solubility can be relatively expensive to manufacture. Thus during manufacture, the dissolution rate of each batch of formulated compound must be tested against a dissolution specification to ensure consistency and compliance. Examples of such dissolution specifications are contained in the United States Pharmacopeia (USP) and the British Pharmacopoeia (BP). Batches that fail to pass the specification must be rejected. Formulations in which the dissolution rate of a compound is relatively close to the specification exhibit a relatively higher incidence of failed batches due to manufacturing variability. It is generally desirable to have a formulation that routinely passes the dissolution specification by a wide margin.
It is apparent that the compositions of the formulations of commercially available tamoxifen citrate vary around the world. For example, in the United States, NOLVADEX.RTM. 10 mg (produced by Zeneca Pharmaceuticals, Wilmington Del., USA) is reported in the U.S. Physicians Desk Reference, 50.sup.th Edition 1996 (see above) to be formulated with carboxymethylcellulose calcium, magnesium stearate, mannitol and starch. In Europe, the Italian Directory of Medicines, 1994 (OEMF spa, Via Edolo- 20125 Milano) reports that NOLVADEX.RTM. D 20 mg (produced by Zeneca Limited, Macclesfield Cheshire, United Kingdom) contains tamoxifen citrate (30.4 mg), lactose (234 mg), starch (82.2 mg), gelatin (2.2 mg), croscarmellose sodium (7.2 mg), magnesium stearate (4.0 mg), hydroxypropylmethylcellulose (5.4 mg), polyethyleneglycol ("macrogol") (1.1 mg), and titanium dioxide (1.6 mg), the latter three ingredients presumably forming a coating for the tablet. The 10 mg formulation has half the weight of each ingredient.